Autoclavable multilayer films

ABSTRACT

An autoclavable multi-layer film formed of thermoplastic materials capable of being processed into hollow shapes and useful for packaging oxygen sensitive materials. The film includes sequential layers A--B--C--D--C--B&#39;--A&#39;, wherein the film may optionally not include layer A or A&#39; and the corresponding layer B or B&#39;. A and A&#39; are layers substantially water and water vapor resistant, wherein at least one of the layers A and A&#39; is made of polyolefins, polyethylene terephthalates, or co-polymers of polyethylene terephthalates. B and B&#39; are layers adhesively bonding layers A and A&#39; with layers C. C is a layer of a moisture absorbing polymer substantially impermeable to oxygen. The polymer is selected from the group consisting of aromatic polyamides and co-polymers of aromatic polyamides. D is a layer of a polyethylene-vinyl alcohol with a molar ethylene concentration between 0% and 80%.

FIELD OF INVENTION

The present invention relates to novel autoclavable multilayer films ofpolymeric materials, packages and flexible containers made thereof aswell as a process for the production of such articles and the use of thefilms. The articles made from the novel multilayer films are especiallysuitable to contain oxygen sensitive medical or nutritional fluids forparenteral or enteral administration, because they retain both theirtransparency and oxygen barrier properties after autoclavation.

BACKGROUND OF THE INVENTION

It has been a considerable technical problem for manufacturers ofmaterials for medical containers or packages to provide an autoclavablematerial compatible with infusion fluids often containing fat emulsions,to be administrated parenterally. It is especially desirable to retainflexibility and transparency of the material after the autoclavationwhile simultaneously meeting the demand of having an oxygen and waterbarrier for the protection of sensitive contents during storage.

Another problem to be solved is to find a polymer material whichfulfills these criteria and still is environmental friendly and withoutany hazards for the manufacturers.

In many medical materials polymer materials such as those prepared fromhalogenated hydrocarbons like PVC or PVDC have traditionally been used,since they often have low permeability for water and gases and haveadvantageous mechanical properties. Medical plastic bags made from PVCare, however, undesirable because medical fluids may dissolve softenersfrom the PVC, making them incompatible with many requirements inpharmaceutical applications. Such migration effects can be especiallyproblematic when storing fat emulsions which tend dissolve hydrophobiccomponents from the polymers. PVC and other polymers from halogenatedhydrocarbons are also unsuitable for other technical reasons, like theirtendency to corrode and to wear the manufacturing equipment, and becauseof their environmental hazards. To overcome these drawbacksmanufacturers have tried to assemble substitute packaging materials inthe form layered structures, where the properties of each of the layersare intended to support the others to achieve air and waterimpermeability, suitable mechanical properties and a possibility tosterilize the package material and its contents by steam or byirradiation.

Steam-sterilizable multilayer materials are disclosed in numerouspublications. A typical simple multilayer film fulfilling this technicalrequirement consists of three layers: polyolefin/polyamide/polyolefin.The polyolefin layer acts as a water barrier and the polyamide can beboth moisture resistant and act as a substantial oxygen barrier.However, this type of film is not sufficiently effective as a moisturebarrier. More efficient films are developed in the patent specificationsEP 0216 639 and U.S. Pat. No. 4,407,897.

The European patent application EP 0457 648 discloses a moresophisticated type of film with different polymer barrier layers havingcomplementary properties. In applications with extremely rigorousrequirements, like storage of materials for parenteral administration inmedicine, not even these films are satisfying in terms of oxygen barriershaping qualities.

EP 0236 099 discloses a sterilizable seven layer film with oxygenbarrier characteristics having the structure A/B/C/D/C/B/A, where A isan outer layer, B is an adhesive layer, C is an intermediate layer, andD is barrier core layer. The barrier core layer, D, is preferably madefrom ethylene vinyl alcohol polymer and is surrounded by two moistureabsorbing nylon containing moisture absorbing layers C. The outer layersA, preferably consist of a copolymer of a polyolefin, such as apolyethylene with an unsaturated carboxylic acid or acid anhydride. Themoisture absorbing nylon layers, C, will however, include nylon 6, whichmakes the film unsuitable for medical applications due to the risk of aneventual caprolactam release which is regarded as a hazardouscontribution to parenterally administerable fluids. Nylon containingfilms also have a tendency to become opaque after heat sterilizationwhich can give the resulting product an undesired appearance. Besidesthese drawbacks, the films of EP 0236 099 seem to be excessively stifffor convenient handling and manufacturing. Additionally, articles madefrom the film will not be easy to open because that there will not beany peel effect between the outer layers A.

The abstract of the Japanese patent application 3087254 reveals alaminate with good oxygen barrier properties composed a copolymerpolyamide layer containing structural units from meta-xylene polyamide,a polyolefin layer and/or an EVOH layer. This film will, however sufferfrom the disadvantage of becoming opaque after autoclavation and it willalso lack the peel effect between its outer layers.

Consequently, there is still a great demand for improved steamsterilizable multilayer materials with very low oxygen permeability forpackaging perishable medical and/or nutritional fluids for parenteraladministration in a single primary package with excellent transparency.

SUMMARY OF THE INVENTION

The invention intends to provide a multilayer film, which issubstantially impermeable to oxygen and autoclavable, while havingflexible properties suitable for further processing and manufacturing topackages, containers and other shapes to be filled with oxygen sensitiveand perishable goods, as well as having the benefit of a highaesthetical value, due to its retention of transparency afterautoclavation.

The invention is also directed to flexible containers or medicalpackages containing medical or nutritional material made from the novelmultilayer film, as well as processes for their manufacture and the useof the novel film for the manufacture of such articles.

A further object of the invention is a process for the preparation ofthe multilayer film by sequentially laminating together the differentlayers.

The multilayer film is most readily described by the general sequentialpalindrome formula A--B--C--D--C--B'--A', wherein each capital lettersymbol corresponds to a unique layer of the film.

The layers are all made of polymeric materials with characteristicchemical and physical properties and are generally described as followspart. The outermost layers A and A' front the environment and theperishable goods inside a container made from the multilayer film. Incertain applications, when the multilayer film is used as a wrapping foranother container, either A or A' faces a bag or a primary containerfilled with the perishable goods. The multilayer film will, in suchcases be formed as an envelope or a secondary container filled with aninert atmosphere and a primary container before sealing.

A and A' shall be made from a moisture resistant material capable ofwithstanding both water vapor and liquid water. These layers can be madefrom the same or different polyolefines or PET(polyethylene-terephtalate) or copolymers of PET. Preferred polyolefinesare polyethenes and polypropylenes with moisture barrier qualities. Itis especially preferred to select polyolefines which form a weak sealwelding with each other so that peelable contact surfaces will be formedwhen autoclaving the film. In such cases the layers A and A' shall bemade from polymers compatible with each other, so molecules in theircontact surfaces can interdiffuse under the influence of heat.

The one of layers A or A' which faces the environment can be removed ina special embodiment of the invention, to further increase theflexibility of the multilayer film, and to provide a surface suitablefor welding. In this case the subsequent adhesive layer B will also beremoved.

The layers B and B' are adhesive layers or tie-layers providing adhesivebonding between layers A and A' and layers C. The nature of such a layercan be easily determined and chosen by anyone aware of the polarity oflayers A and A' and C. For example, B must be a significantlyhydrophilic polymer if the other fronting layers are hydrophobic.

The layers C are made from polymers with moisture absorbing qualitiesand are substantially impermeable for oxygen, thus providing a barrierfor oxygen. Especially suitable polymers are found among aromaticpolyamides or derivatives or copolymers thereof which can absorbmoisture and increase their density and thereby substantially contributeto the oxygen barrier. It also an important requirement that thepolyamides are totally biocompatible and not release caprolactams andother potentially hazardous compounds to the stored materials.

The layer D consists of poly(ethylene)-vinyl alcohol (EVOH), which is amaterial with excellent oxygen barrier qualities as long as it is dry.The EVOH-layer has hydrogen bondings between its hydroxide moleculeswhich will be destroyed by penetrating water molecules, so that oxygencan leak through the layer and its barrier function decays rapidly.

The multilayer film assembled with layers according to above, willprovide a surprisingly effective oxygen and moisture barrier both duringautoclavation at about 120° C. and during storage for the protection ofperishable material such as parenteral infusion fluids.

The inventive multilayer film is constructed especially to prevent theEVOH from losing its effect as an oxygen barrier. EVOH, will aspreviously explained, be an excellent barrier for oxygen in a drycondition.

In previous applications of EVOH, such a film is bonded to a moistureprotecting layer of, for example, polyolefines. The protectingpolyolefin layers are sufficient for use under normal conditions, butautoclaving leads to an increase in oxygen penetration which will causea permanently decreased oxygen barrier quality of the EVOH. Besidesthat, the autoclaving conditions will lead to a whitening effect whichdeteriorates the transparency of the film.

According to the present invention the EVOH-layer therefore issurrounded with two layers of a polyamide including aromatic groups (ora derivative or a copolymer thereof) acting as a moisture absorbentwhich will absorb water corresponding to the dynamically cycle of thesterilization in an autoclave. Together with the water resistant layersA and/or A' and the adhesive layers B and/or B', the multilayer film isan optimally assembled film, balancing the kinetics of the steamsterilization. It means that the EVOH-layer will be protected fromwater, because water will never have the opportunity to pass theprotective layers A and/or A' and C.

The layers C, consisting of an aromatic polyamide (or a derivative orcopolymer thereof), both contribute to the oxygen barrier and to themoisture barrier, because of its moisture absorbing quality.

An advantage with the multilayer film according to the present inventionwith the specifically selected layers C is that pure EVOH can be usedwithout any compatibilisers, such as nylon, which lead to decreasedrisks for migration effects during the storage of fluids.

Another advantage compared to conventional films made frompolypropylene/EVOH/polypropylene is that the drying step becomessuperfluous. The novel films will immediately provide an excellentoxygen barrier after autoclavation and not be subjected to irreversiblebarrier losses.

The layers A and/or A' are essentially moisture barriers, preventingwater to reach the EVOH-layer through the polyamide layers, preferablychosen to form weak seal weldings when heated to form peelable surfaces.

The inventive multilayer film material can be assembled withconventional processing methods as coextrusion or laminating. Theconditions for manufacturing processess of the film will vary with thematerials used as layer components, but can easily be found out bypersons smiled in the art. The multilayer film material according to theinvention is also easy to process into hollow shapes as sealable,flexible or collapsible containers packages, bags or pouches etc. byconventional means and methods.

Medical packages manufactured from the film will preferably containsterilizable, but perishable goods, in the form of fluids or solidmaterial to be mixed with such fluids. The goods stored in such packagesare intended to be administered parenterally or enterally fortherapeutical and/or nutritional purposes.

Examples of such fluids or materials are lipid emulsions, amino acids,glucose and other carbohydrates, vitamins, electrolytes, trace elementsor any mixture thereof. These components may be stored together orstored separately in a multi-compartment package prepared from theinventive multilayer film. The medical packages according to theinvention can be aseptically filled with the fluids or materialsmentioned above and will thereafter be sealed by conventional sealingmeans, for example, by welding, and finally subjected to heatsterilization in an autoclave.

In other applications, for example when especially heat sensitive andperishable goods shall be stored, it can be suitable to fill theperishable goods aseptically in a primary, inner container principallymade of one or plural layers of an at least partially oxygen permeablepolymer like EVA poly(ethylene)-vinyl acetate), which is sealed andsterilized by irradiation. In other applications can of course theprimary, inner container be sterilized by other means such as steam. Theprimary container is thereafter placed in an envelope formed by themultilayer film according to the invention, air is evacuated by vacuumgenerating means and atmospheric pressure restored by an inert gasbefore sealing the envelope. All types of containers, bags or envelopesdisclosed herein can be manufactured as both one-, two- three- ormulti-compartment containers provided with means for communicationbetween the compartments, so their components can be mixed immediatelybefore dispensing the contents of the containers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a schematic cross sectional view of an embodiment ofthe film according to the invention. The capital letter symbol in thefigure corresponds to the symbols and layers used elsewhere in the text.

FIG. 2 shows a comparison of weight changes of different multilayeredfilms and a film according to the invention.

FIGS. 3 and 4 show the change in absorbance for products stored indifferent multilayered films compared to a film according to theinvention.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Multilayer films according to the invention described with the generalschematic formula A--B--C--D--C--B'--A' will preferably be composed byindividual layers as desribed below.

The outer water and water vapor resistant layers A and A', of which oneoptionally could be removed, can be made of polyolefines,polyethyleneterephtalates (PET) or copolymers of PET. Suitablepolyolefines are polyethenes and polypropylenes. The polyolefines shouldbe both moisture resistant and resistant for sterilization byirradiation, examples of such a materials are the polypropylene WB8052Cfrom Neste and various polyethenes. Polypropylene is especiallypreferred if the multilayer film shall be subjected to steamsterilization, but if sterilization by irradiation is for some reasondesirable, polyethenes are the suitable choice for layers A and A',since polypropylenes are not sterilizable with irradiation. It is alsopossible to use copolymers of polypropylenes and polyethenes in theselayers. It is especially preferable to choose such polypropylenes havingqualities that are capable of forming weak weldings between such layersA and/or A', when heating the material, for example, duringautoclavation. The effect will be a ready peelable surface between suchlayers A and/or A'. Persons skilled in the technique will not have anydifficulties to find suitable materials for the outer layers accordingto the guidelines presented above. The thickness of outer layers A andA' are preferably 20-100 μm and most preferably 45-55 μm.

The adhesive layers or "tie-layers" B will be chosen from materialsproviding adhesive bonding with both layers A/A' and layers C. Aspreviously mentioned above, layers B and B' are chosen with respect tothe polarity of the surrounding layers, which shall be bonded together.Examples of material suitable for binding polyethenes and polyamidestogether are Dow Prima Cor 16105 and Admer® QF500E, which arepolypropylene modified maleic acid anhydrides. The layers B and B' shallbe about 10 μm in thickness. Alternatively, layers B and B' have athickness of between 2 to 30 μm each and preferably between 5 and 25 μm.If layers A/A' consist of polypropylene is Admer® QF55IE a suitablechoice as a binding layer.

The layers C consist of moisture absorbent and oxygen barrier shapingaromatic polyamides or derivatives or copolymers thereof and have apreferred thickness of 20-100 μm, most preferably between 30-40 μm. Oneexample of a material appropriate according to the invention is madefrom a composition of 80% Nyref® MXD-6 from Mitsubishi with a meltingpoint of 245° C. consisting of a copolymer of metaxylenediamine andadipidic acid and 20% of XE 3303 from EMS-Chemie, which is a copolymerof hexamethyleneadinine and adipidic acid or a copolymer of adipidicacid, hexamethyleneadinine and sepaic acid. Copolymers of the mentionedMXD6 and XE 3303 are also conceivable according to the invention. Anexample of another suitable composition consists of the mentioned MXD6of grade 6007 and Polyamide 66 (PA66), (a copolymer ofhexamethyleneadinine and adipidic acid), with less than 1.3 in relativeviscosity. It is also suitable that the polymers of layers C include anaromatic acid having two acid groups combined with an aromatic aminehaving two amino groups.

The principal oxygen barrier layer D of the multilayer is made ofpolyethylene vinyl/alcohol (EVOH) with a thickness of 2-40 μm,preferably about 20 μm. The molar ethylene concentration in the EVOH canvary from 0-80% (0% means PVOH, polyvinyl alcohol), preferably between10-50%. An appropriate quality for this layer is BX220 from Dupont witha molar ethene concentration of 33%.

A preferred embodiment of the multilayer film is polyethen (A)/adhesivelayer made of Dow Prima Cor 16105 (B)/layer made of 80% MDX-6 and 20% ofXE 3303 (C)/layer of the EVOH BX 220 (D)/same as previous (C)/same asprevious (B)/same as previous (A). For the exact definitions of thecomponents of the layers reference is made to the text above.

The examples of the components of the layers are not intended to belimiting. Any person skilled in the art of polymer materials can easilyfind appropriate and well functioning alternatives to the componentsexemplified in this text within the scope of invention as it is definedby the claims.

The following studies intend to compare the oxygen permeability, thewater permeability and the material weight before and after autoclavingbetween the inventive multilayer film and other film materials.

The seven tested film materials are:

Film 1: polypropylene (PP)/EVOH; 30% ethene/polypropylene (PP)

Film 2: PP/EVOH; 44% ethene/PP

Film 3: PP/polyamide: XE 3303 (PA)/PP

Film 4: Polyethen (PE)/PA (as in Film 3)/PE

Film 5: PE/polyamide: 80% MXD6 and 20% XE 3303 (PA)/EVOH; 33% ethene/PA(same)/PE

Film 6: PP/PA (polyamide 6)/a copolymer containing EVOH/PP

Film 7: Polytehyleneterephtalate (PET)/glass/PET/PP

The adhesive or "tie-layers" between layers of the exemplified filmshave not been included in the schematic comparison above. Forinformation about the polyamide materials in Films 3-5, see the detaileddescription above. Film 5 is an example of a multilayer materialaccording to the present invention.

Films 1-5 have been manufactured by Wihuri Oy Wipak Medical and Films6-7 are supplied by Soplaril S.A.

Film 6 is an example of a material disclosed in the European PatentApplication EP 0457 648.

Table 1 shows the oxygen permeability measured in cubic centimeters persquare meter, day and bar for Films 1-7 at different temperatures anddifferent relative humidity.

                  TABLE 1                                                         ______________________________________                                        Permeability (before sterilization)                                                   Ox. 23° C./60% RH                                                                 Ox. 50° C./>95% RH                                          cc/m.sup.2,day,bar                                                                       cc/m.sup.2,day,bar                                         ______________________________________                                        Film 1    <0.5         8.50                                                   Film 2    5.00                                                                Film 3    38.00        195.00                                                 Film 4    37.00        175.00                                                 Film 5    0.50         4.50                                                   Film 6                 6.00                                                   Film 7    0.84         5.00                                                   ______________________________________                                    

The results from Table 1 indicate that Film 5, prepared according to thepresent invention, has the best oxygen barrier properties of thecompared multilayered films.

FIG. 2 presents weight changes before and after autoclavation of pouchesmade from Films 1 and 3-7. The pouches were weighed before and afterautoclavation, wrapped around an inner bag and once again autoclave. Theinner bag was removed and the pouch wiped dry. The pouches were weighedagain after 1 hour, 24 hours and one week, respectively.

The results from this test show that Film 5 according to the presentinvention absorbs more moisture and retains it much longer (has lowerweight reduction) than the other films. This can be explained by thedouble polyamide layers of Film 5 absorbing more water and holding itlonger. It is however, surprising that this film has such a low oxygenpermeability. This phenomenon can be explained by that the PA-layersabsorb so much moisture during the autoclavation that it never reachesthe EVOH in the interior of the film.

FIGS. 3 and 4 show the absorbance measured at 430 nm after six weeks andthree months storage of Vamin 18® (an amino acid mixture useful inparenteral nutrition) in containers manufactured from Films 1 and 3-7and in comparison to traditional storage materials as glass bottles andaluminum foil. The absorbance value will be a measure of the oxygenpenetration of the film. The increase in absorbance is derived fromoxygen dependent dimerization of certain amino acids in Vamin 18®.

As shown in FIGS. 3 and 4, Film 5 according to the invention hassuperior properties regarding oxygen penetration compared to the otherfilm materials and comparable to the traditional materials.

The advantageous results of the film according the invention must becredited to the surprisingly successful efforts to combine theproperties of the different layers. Especially in terms of providing anefficient moisture barrier with moisture absorbent propertiessurrounding the principal oxygen barrier layer D of EVOH. The inventivemultilayer film can be seen as effort to provide art ideal environmentfor layer D, so its oxygen barrier properties are constant even duringand after autoclavation.

We claim:
 1. An autoclavable multi-layer film formed of thermoplasticmaterials capable of being processed into hollow shapes and useful forpackaging oxygen sensitive materials, comprising:sequential layersA--B--C--D--C--B'--A', wherein the film may optionally not include layerA or A' and the corresponding layer B or B', and wherein: A and A' arelayers substantially water and water vapor resistant, wherein at leastone of the layers A and A' is made of polyolefins, polyethyleneterephthalates, or co-polymers of polyethylene terephthalates; B and B'are layers adhesively bonding layers A and A' with layers C; C is alayer of a moisture absorbing polymer substantially impermeable tooxygen, said polymer being selected from the group consisting ofaromatic polyamides and co-polymers of aromatic polyamides; and D is alayer of a polyethylene-vinyl alcohol with a molar ethyleneconcentration between 0% and 80%.
 2. A film according to claim 1,wherein layer C includes at least one aromatic polyamide which is aco-polymer of hexamethyleneadinine or metaxylenediamine.
 3. A filmaccording to claim 1, wherein layer C includes at least one aromaticpolyamide that was polymerized from an aromatic acid having two acidgroups and an aromatic amide having two amino groups.
 4. A filmaccording to claim 1, wherein at least one of the layers A and A' ismade of polyethylene, polypropylene, or copolymers thereof.
 5. A filmaccording to claim 1, wherein the polyethylenevinyl alcohol with a molarethylene concentration between 10% and 50%.
 6. A film according to claim1, wherein layers A and A' each have a thickness of between 20 and 100μm, layers B and B' each have a thickness of between 2 and 30 μm, layersC each have a thickness of between 20 and 100 μm, and layer D has athickness of between 2 and 40 μm.
 7. A film according to claim 1,wherein layers A and A' each have a thickness of between 45 and 55 μm,layers B and B' each have a thickness of between 5 and 25 μm, layers Ceach have a thickness of between 30 and 40 μm, and layer D has athickness of between 15 and 25 μm.
 8. A film according to claim 1,wherein said film is transparent and a barrier to oxygen afterautoclavation.
 9. A flexible container manufactured from a multilayeredfilm according to claim
 1. 10. A flexible container according to claim9, wherein said container contains sterilizable medical or nutritionalfluids.
 11. A flexible outer package for at least one of medical andnutritional uses manufactured from a multilayered film according toclaim 1 and contains parenterally administered fluids.
 12. A flexibleouter package for at least one of medical and nutritional usesmanufactured from a multilayered film according to claim 1 and containsparenterally administered fluids in a primary inner package.
 13. Aprocess for manufacturing a medical package according to claim 11,wherein said package is aseptically filled with said fluids, sealed withsealing means, and subjected to steam sterilization.
 14. A filmaccording to claim 2, wherein layer C contains at least one aromaticpolyamide that was polymerized from an aromatic acid having two acidgroups and an aromatic amide having two amino groups.
 15. A filmaccording to claim 2, wherein at least one of layers A and A' is made ofpolyethylene, polypropylene or copolymers thereof.
 16. A film accordingto claim 3, wherein at least one of layers A and A' is made ofpolyethylene, polypropylene or copolymers thereof.
 17. A film accordingto claim 2, wherein the molar ethylene concentration of thepolyethylene-vinyl alcohol in layer D is between 20 to 50%.
 18. A filmaccording to claim 3, wherein the molar ethylene concentration of thepolyethylene-vinyl alcohol in layer D is between 20 to 50%.